Stacking Exercises Aid the Decline in FVC and Sick Time

Phase 4

Completed

• Conditions: Duchenne Muscular Dystrophy
• Interventions: Other: Conventional Treatment; Device: Lung Volume Recruitment (LVR)

• Registration Number: NCT01999075
• Lead Sponsor: Children's Hospital of Eastern Ontario

Brief Summary

Duchenne Muscular Dystrophy is complicated by weak breathing muscles and lung infections. "Lung volume recruitment" is a technique performed using a face mask or mouthpiece and a hand-held resuscitation bag to stack breaths, inflate the lungs and help clear the airways of secretions by increasing the forcefulness of a cough. We believe this will slow down the steady loss of lung function, prevent lung infection, and improve quality of life. Our aim is to compare the outcome of a group of individuals with DMD treated with standard care to another group that also receives lung volume recruitment. If effective, this study will change clinical practice by including twice-daily treatment as part of the standard of care for individuals with DMD, in order to improve their lung health and quality of life.

Detailed Description

Background: Respiratory complications are the primary cause of morbidity and mortality associated with childhood Duchenne Muscular Dystrophy (DMD). Involvement of the respiratory muscles leads to progressive hypoventilation and/or recurrent atelectasis and pneumonia secondary to decreased cough efficacy. Lung volume recruitment (LVR) is a means of stacking breaths to achieve maximal lung inflation (MIC), prevent micro-atelectasis, and improve cough efficacy. Although it has been recommended by some experts as the "standard of care" for individuals with neuromuscular disease, the strategy has not been widely implemented in DMD given the lack of clinical trials to date to support its efficacy as well as the additional burden of care required in a population already requiring multiple interventions.

Primary Objective: To determine whether LVR, in addition to conventional treatment, is successful in reducing decline from baseline in forced vital capacity (FVC) over 2 years (percent predicted, measured according to American Thoracic Society standards), compared to conventional treatment alone in children with DMD.

Secondary Objectives: To determine differences between children treated with LVR in addition to conventional treatment, compared to those treated with conventional treatment alone, in: (1) the number of courses of antibiotics, hospitalizations and intensive care admissions for respiratory exacerbations, (2) health-related quality of life, and (3) peak cough flow and other pulmonary function tests.

Methods: We propose a 3-year multi-centre randomized controlled trial involving fifteen tertiary care pediatric hospitals across Canada. The study population consists of boys aged 6-16 years with DMD and FVC ≥ 30% of predicted. A sample size of 110 participants will be enrolled. This has been informed by chart review and survey of participating centres to be feasible, and will be re-assessed with an ongoing internal pilot study. Intervention: Participants will be allocated with a minimization procedure to receive conventional treatment (non-invasive ventilation, nutritional supplementation, physiotherapy and/or antibiotics, as decided by the treating physician) or conventional treatment plus twice daily LVR exercises performed with an inexpensive, portable self-inflating resuscitation bag containing a one-way valve and a mouthpiece. Data Analysis: The primary outcome (change in percent predicted FVC over 2 years) will be compared between the two study groups using an analysis of co-variance (ANCOVA) that takes into account baseline FVC and minimization factors.

Importance: Decline in pulmonary function among children with DMD negatively affects quality of life and predicts mortality. The relatively simple strategy of LVR has the potential to optimize pulmonary function and reduce respiratory exacerbations, thereby improving quality of life for individuals with DMD. This study is novel in that it is the first randomized controlled trial of LVR. A major strength is that the results will give support or refute recommendations regarding inclusion of LVR in the standard of care for individuals with DMD worldwide.

Study Timeline

• Study Start: 2013-03
• Study First Submitted: 2013-11-14
• Study First Submitted QC: 2013-11-25
• Study First Posted: 2013-12-03
• Primary Completion: 2018-11-22
• Study Completion: 2018-11-22
• Results First Submitted: 2021-09-08
• Status Verified: 2024-11
• Results First Submitted QC: 2024-11-22
• Last Update Submitted: 2024-11-22
• Results First Posted: 2025-01-09
• Last Update Posted: 2025-01-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 70

Inclusion Criteria

• Age 6-16 years - This age range was selected as there are accepted normative pulmonary function data and children 6 years of age and older are generally able to reliably perform pulmonary function tests. Children are followed in participating centres until they reach 18 years of age (allowing two years of follow-up).
• Clinical phenotypic features consistent with DMD and confirmed by either: (1) Muscle biopsy showing complete dystrophin deficiency; (2) Genetic test positive for deletion or duplication in the dystrophin gene resulting in an 'out-of-frame' mutation; or (3) Dystrophin gene sequencing showing a mutation associated with DMD.
• FVC ≥ 30% predicted - This range of pulmonary function was selected to exclude those with severe restrictive respiratory impairment, who are less likely to be able to reliably perform pulmonary function testing over a two year period.
• A caregiver willing to provide the therapy
• Fluency in English or French

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Exclusion Criteria

• Unable to perform pulmonary function tests and/or LVR manoeuvre
• Presence of an endotracheal or tracheostomy tube
• Already using LVR and/or the Respironics in-exsufflator between and during respiratory infections
• Known susceptibility to pneumothorax or pneumomediastinum
• Uncontrolled asthma or other obstructive lung disease
• Symptomatic cardiomyopathy (ejection fraction less than 50% )

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Conventional Treatment	Conventional Treatment	Conventional Treatment
Lung Volume Recruitment	Conventional Treatment	Conventional treatment plus the use of Lung Volume Recruitment (LVR) twice per day
Lung Volume Recruitment	Lung Volume Recruitment (LVR)	Conventional treatment plus the use of Lung Volume Recruitment (LVR) twice per day

Primary Outcome Measures

Name	Time	Method
Change in FVC (%-Predicted) From Baseline to 2 Years.	2 years	Change in FVC (%-predicted) was chosen as the primary outcome as it is a strong predictor of subsequent respiratory failure and mortality. Although survival is not a realistic endpoint for this trial, given expected mortality is less than 5% for the pediatric age group, FVC change is an appropriate clinical laboratory measure and valid surrogate endpoint to use for this trial.

Secondary Outcome Measures

Name	Time	Method
FVC Decline of 10% of Predicted	2 years	The time to reach an FVC decline of 10% of predicted will be used to calculate a hazard ratio.
Number of Participants Prescribed Outpatient Oral Antibiotic Courses Between Baseline and 2 Years	2 years	Total number of participants who received any antibiotic courses between baseline and two years
Health-related Quality of Life From Baseline to 2 Years	2 years	Measured biannually using the Pediatric Quality of Life Inventory (PedsQL 4.0). The PedsQL includes four subscales: Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning. Each subscale is scored from 0 to 100, with higher scores indicating better health-related quality of life. A total score is computed by averaging all subscale scores.
Change in Difference Between Assisted and Unassisted Peak Cough Flow (PCF) From Baseline to 2 Years	2 years	Change in the difference between assisted and unassisted peak cough flow (in liters per minute) from baseline to 2 years.
Change in Maximal Insufflation Capacity (MIC)-Vital Capacity (VC) From Baseline to 2 Years	2 years	Change in maximal insufflation capacity (MIC)-vital capacity (VC) in liters from Baseline to 2 Years
Change in Maximum Inspiratory Pressures (MIP), From Baseline to 2 Years	2 years	Change in maximum inspiratory pressures (MIP, in centimeters of water), From Baseline to 2 Years
Change in Maximal Expiratory Pressures (MEP), From Baseline to 2 Years	2 years	Change in maximal expiratory pressures (MEP, in liters), From Baseline to 2 Years

Trial Locations

Locations (9)

London Health Sciences; 🇨🇦 London, Ontario, Canada

SickKids Hospital; 🇨🇦 Toronto, Ontario, Canada

Alberta Children's Hospital; 🇨🇦 Calgary, Alberta, Canada

Children's Hospital of Eastern Ontario; 🇨🇦 Ottawa, Ontario, Canada

Holland Bloorview Kids Rehabilitation Hospital; 🇨🇦 Toronto, Ontario, Canada

Stollery Children's Hospital; 🇨🇦 Edmonton, Alberta, Canada

BC Children's Hospital; 🇨🇦 Vancouver, British Columbia, Canada

Hôpital Ste. Justine; 🇨🇦 Montreal, Quebec, Canada

McMaster University; 🇨🇦 Hamilton, Ontario, Canada